1-15518120-A-G

Variant names:

• chr1-15518120-A-G
• rs1132312
• NM_001229.5:c.408T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001229.5(CASP9):​c.408T>C​(p.Phe136Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,613,430 control chromosomes in the GnomAD database, including 236,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.59 (26847 hom., cov: 32)
  • Exomes 𝑓: 0.53 (209433 hom.)
• Consequence: CASP9 NM_001229.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.325
• Publications: 21 publications found

Genes affected

CASP9 (HGNC:1511): (caspase 9) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein can undergo autoproteolytic processing and activation by the apoptosome, a protein complex of cytochrome c and the apoptotic peptidase activating factor 1; this step is thought to be one of the earliest in the caspase activation cascade. This protein is thought to play a central role in apoptosis and to be a tumor suppressor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-15518120-A-G is Benign according to our data. Variant chr1-15518120-A-G is described in ClinVar as Benign. ClinVar VariationId is 3058888.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.325 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001229.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_001229.5	MANE Select	c.408T>C	p.Phe136Phe	synonymous	Exon 2 of 9	NP_001220.2
	CASP9	NM_032996.3		c.159T>C	p.Phe53Phe	synonymous	Exon 2 of 9	NP_127463.2
	CASP9	NM_001278054.2		c.408T>C	p.Phe136Phe	synonymous	Exon 2 of 5	NP_001264983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.408T>C	p.Phe136Phe	synonymous	Exon 2 of 9	ENSP00000330237.5
	CASP9	ENST00000348549.9	TSL:1	c.408T>C	p.Phe136Phe	synonymous	Exon 2 of 5	ENSP00000255256.7
	CASP9	ENST00000400777.7	TSL:1	n.399T>C		non_coding_transcript_exon	Exon 2 of 9	ENSP00000383588.3

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89138 AN: 151956 Hom.: 26808 Cov.: 32

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.532 AC: 133590 AN: 251268 AF XY: 0.526

Gnomad AFR exome AF: 0.701

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.648

Gnomad FIN exome AF: 0.645

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.532 AC: 777148 AN: 1461358 Hom.: 209433 Cov.: 54 AF XY: 0.529 AC XY: 384670 AN XY: 726904

African (AFR) AF: 0.704 AC: 23555 AN: 33470

American (AMR) AF: 0.419 AC: 18732 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 13030 AN: 26130

East Asian (EAS) AF: 0.645 AC: 25583 AN: 39690

South Asian (SAS) AF: 0.432 AC: 37296 AN: 86248

European-Finnish (FIN) AF: 0.638 AC: 34076 AN: 53414

Middle Eastern (MID) AF: 0.510 AC: 2927 AN: 5742

European-Non Finnish (NFE) AF: 0.530 AC: 589383 AN: 1111568

Other (OTH) AF: 0.539 AC: 32566 AN: 60372

GnomAD4 genome AF: 0.587 AC: 89222 AN: 152072 Hom.: 26847 Cov.: 32 AF XY: 0.587 AC XY: 43652 AN XY: 74338

African (AFR) AF: 0.705 AC: 29268 AN: 41498

American (AMR) AF: 0.498 AC: 7608 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1732 AN: 3468

East Asian (EAS) AF: 0.646 AC: 3341 AN: 5168

South Asian (SAS) AF: 0.425 AC: 2050 AN: 4824

European-Finnish (FIN) AF: 0.652 AC: 6892 AN: 10572

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36545 AN: 67950

Other (OTH) AF: 0.552 AC: 1167 AN: 2114

Alfa AF: 0.538 Hom.: 30418

Bravo AF: 0.581

Asia WGS AF: 0.553 AC: 1923 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.516

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CASP9-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.41
PhyloP100		-0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1132312; hg19: chr1-15844615; COSMIC: COSV61601103; COSMIC: COSV61601103;